The prognosis of patients suffering myocardial infarction or malignant tumors depends on early diagnosis and intervention. Therefore, medical practitioners wish to obtain improved imaging methods to facilitate early, accurate diagnosis of serious health conditions, such as myocardial infarcts and tumors.
Previous reports suggest that various glucose analogs (glucoheptonate, gluconate, glucarate) labeled with Tc-99m may be useful for the detection of tumors and acute tissue injury [1-8]. More recently, Tc-99m-labeled glucarate, a six carbon dicaroxylate sugar, was found to accumulate in both experimental tumors and in acute myocardial infarction [9-12].
In several clinical and preclinical investigations, Tc-99m-glucarate has recently been documented to be preferentially retained by necrotic tissue [10-12]. Tc-99m-glucarate localization was significantly greater in necrotic cells compared to normal control cells and ischemic viable cells [11]. It has been suggested that this agent may be useful in the early detection of necrotic myocardium and differentiation from ischemic myocardium in patients with acute onset of chest pain [10, 12].
The exact mechanism of Tc-99m-glucarate localization is currently not known. However, it was shown in a cell culture system that presence of fructose reduced the accumulation of Tc-99m-glucarate in hypoxic cells but had no effect on accumulation in aerobic cells [3, 13]. A proposed mechanism of uptake is based on decreased availability of oxygen causing an increased extraction of Tc-99m-glucarate in tumor and ischemic tissues via an anaerobic pathway [13].
Ballinger, et al. reported that under hypoxia, the presence of fructose reduced the accumulation of Tc-99m-glucarate by 30% and Tc-99m-gluconate by 40% in Chinese hamster ovary cells, but had no significant effect on accumulation of these Tc-99m-labeled carbohydrates in aerobic conditions [13]. Based on these observations, together with the exclusion of Tc-99m-DTPA by hypoxic cells, these authors suggested that cell membranes were intact and intracellular uptake of Tc-99m-glucarate and Tc-99m-gluconate was related to fructose transport.
Recently, Petrov, et al. reported that Tc-99m-glucarate uptake in a BT-20 human breast tumor model at 5 hours (1.13% ID/g) and at 8 hours (1.21% ID/g) was significantly greater than uptake of Tc-99m-MIBI and Tc-99m-DTPA [9]. They also showed that 50.9% of the intracellular Tc-99m-glucarate accumulated in the nuclei, 34.3% in the cytoplasm, and 14.8% in the mitochondria of the tumor cells.
Orlandi, et al. reported a high affinity binding of Tc-99m-glucarate to necrotic myocardium in dogs with experimental myocardial infarction [8]. However, they found no accumulation of Tc-99m-glucarate in hypoxic but viable myocardium. Likewise, Yaoita, et al. found marked uptake of Tc-99m-glucarate in acute cerebral injury but no uptake in viable tissue [7]. Tc-99m-glucarate concentrated in the center of the cerebral injury while F-18-FDG was decreased in this region. The disparity between distribution of F-18-FDG and Tc-99m-glucarate was interpreted as evidence that Tc-99m-glucarate does not behave as a glucose analog.
Despite promise as possible imaging agents, Tc-99m-glucurate and other Tc-99m-labeled glucose analogs known to the art suffer the disadvantage of unstable Tc-99m labeling. In fact, Tc-99m labeled gluconate and glucarate are used as Tc-99m donor substrates in transchelation reactions to label antibodies and peptides [16,17]. Currently, kits containing Tc-99m-labeled gluconate or glucarate are used in transchelation reactions to label polypeptides. Reduced Tc-99m is transferred to various ligands such as antibodies and peptides from Tc-99m-labeled gluconate or glucarate due to the relatively low binding affinity of Tc-99m for these carbohydrate molecules. The potential for in vivo transfer of Tc-99m from Tc-99m-labeled gluconate or glucarate to polypeptides calls into question the advisability of using Tc-99m-labeled gluconate or glucarate in tissue imaging, because labeling of proteins by Tc-99m may interfere with the normal functioning of the proteins.
Technetium-labeled complexes containing water-soluble mercaptans for use in kidney imaging were disclosed in U.S. Pat. No. 4,208,398.
There is a need for methods and compositions for imaging tumors and acute ischemic tissue injury in humans, and methods that allow recent acute injuries to tissue, such as those caused to heart tissue by recent heart attacks, to be distinguished from normal tissue and older injuries.